Since the genetic risk for alcoholism in humans must be based on the genetic differences in physiological reactions to ethanol, these studies may help in pointing out what those effects are. Independent of this however, the use of animal genetics to study the mechanism of action of ethanol is an important tool in the armamentarium of methods to develop better treatment and prevention measures for humans. This project proposes to continue the selective breeding program to develop rats with a high (HAS) or low (LAS) initial (ie. first dose) sensitivity of the central nervous system to alcohol. The animals have proven useful in elucidating the mechanism by which alcohol depresses the central nervous system. The project has replicated the classic selection for initial central nervous system sensitivity to alcohol in mice, the short- and long-sleep mice (55 and LS) with a much more closely controlled genetic protocol, including replicate and control lines. Currently the lines are still segregating, especially in the direction of the HAS lines. The current results point to a marked difference between the 55 and LS mice in that the rats are differentially sensitive to barbiturates, whereas the LS and 55 mice are not. The rats are also differentially sensitive to halothane, where the mice are not. Since it is thought that these agents act on the major neuronal inhibitory system in the brain, the GABA system, it may be that we have selected a different GABA subunit receptor in the rats than is present in the mice. At a molecular genetic level, this may prove to be helpful in dissecting the effects of ethanol on this system. The rats develop acute tolerance to ethanol. This can be demonstrated behaviorally following a single hypnotic dose of ethanol. We have also demonstrated that the cerebellar Purkinje cells in the behaviorally resistant rats are also resistant to the effects of ethanol on cell firing rates. Experiments to correlate these two findings are planned. The possible role of neurotensin in the acute and chronic effects of ethanol has been investigated. Generally the results replicate that found in the mice. The possible role of neurotensin in tolerance and dependence is planned in the next grant period.